eCD4-Ig Variants That More Potently Neutralize HIV-1

Fetzer, Ina; Gardner, Matthew R.; Davis-Gardner, Meredith E.; Prasad, Neha R.; Alfant, Barnett; Weber, Jesse A.; Farzan, Michael

doi:10.1128/jvi.02011-17

Cited by 23 publications

(23 citation statements)

References 53 publications

(80 reference statements)

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“…Previous studies have shown that incubation of cell-expressed Env trimers with soluble CD4 (sCD4) or CD4-Ig promoted dissociation of gp120 from gp41, a phenomenon described as "shedding" (48). We have previously shown that eCD4-Ig promotes more efficient shedding than CD4-Ig (45). We therefore investigated whether e10-1074 promoted greater shedding than 10-1074.…”

Section: Resultsmentioning

confidence: 95%

“…Here we investigated whether the coreceptor-mimetic peptide mim6 (45) fused to the C termini of bNAbs of various classes could improve their neutralization as it does for CD4-Ig. We observed that mim6 consistently improved the potency of all V3-glycan antibodies tested, whereas it improved the potency of all other bNAb classes only for Envs that could be neutralized by the peptide alone.…”

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confidence: 99%

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A Coreceptor-Mimetic Peptide Enhances the Potency of V3-Glycan Antibodies

Fetzer

Davis-Gardner

Gardner

et al. 2019

J Virol

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Broadly neutralizing antibodies (bNAbs) target five major epitopes on the HIV-1 envelope glycoprotein (Env). The most potent bNAbs have median half-maximal inhibitory concentration (IC50) values in the nanomolar range, and the broadest bNAbs neutralize up to 98% of HIV-1 strains. The engineered HIV-1 entry inhibitor eCD4-Ig has greater breadth than bNAbs and similar potency. eCD4-Ig is markedly more potent than CD4-Ig due to its C-terminal coreceptor-mimetic peptide. Here we investigated whether the coreceptor-mimetic peptide mim6 improved the potency of bNAbs with different epitopes. We observed that when mim6 was appended to the C terminus of the heavy chains of bNAbs, this sulfopeptide improved the potency of all classes of bNAbs against HIV-1 isolates that are sensitive to neutralization by the sulfopeptide alone. However, mim6 did not significantly enhance neutralization of other isolates when appended to most classes of bNAbs, with one exception. Specifically, mim6 improved the potency of bNAbs of the V3-glycan class, including PGT121, PGT122, PGT128, and 10-1074, by an average of 2-fold for all HIV-1 isolates assayed. Despite this difference, 10-1074 does not induce exposure of the coreceptor-binding site, and addition of mim6 to 10-1074 did not promote shedding of the gp120 subunit of Env. Mixtures of 10-1074 and an Fc domain fused to mim6 neutralized less efficiently than a 10-1074/mim6 fusion, indicating that mim6 enhances the avidity of this fusion. Our data show that mim6 can consistently improve the potency of V3-glycan antibodies and suggest that these antibodies bind in an orientation that facilitates mim6 association with Env. IMPORTANCE HIV-1 requires both the cellular receptor CD4 and a tyrosine-sulfated coreceptor to infect its target cells. CD4-Ig is a fusion of the HIV-1-binding domains of CD4 with an antibody Fc domain. Previous studies have demonstrated that the potency of CD4-Ig is markedly increased by appending a coreceptor-mimetic sulfopeptide to its C terminus. We investigated whether this coreceptor-mimetic peptide improves the potency of broadly neutralizing antibodies (bNAbs) targeting five major epitopes on the HIV-1 envelope glycoprotein (Env). We observed that inclusion of the sulfopeptide dramatically improved the potency of all bNAb classes against isolates with more-open Env structures, typically those that utilize the coreceptor CXCR4. In contrast, the sulfopeptide improved only V3-glycan antibodies when neutralizing primary isolates, on average by 2-fold. These studies improve the potency of one class of bNAbs, show that coreceptor-mimetic sulfopeptides enhance neutralization through distinct mechanisms, and provide insight for the design of novel multispecific entry inhibitors.

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Section: Resultsmentioning

confidence: 95%

mentioning

confidence: 99%

A Coreceptor-Mimetic Peptide Enhances the Potency of V3-Glycan Antibodies

Fetzer

Davis-Gardner

Gardner

et al. 2019

J Virol

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“…For instance, Xu et al reported that a trispecific bnAb conferred complete immunity against a mixture of SHIVs in macaques that otherwise show resistance to single monospecific bnAbs (28). Recent studies also demonstrated the robust and sustained antiviral effects of engineered bnAbs with eCD4 as a component, given the fact that all HIV-1 isolates, including those few which can enter cells using only a coreceptor, bind to the primary HIV-1 receptor CD4 (41). In this study, we observed that a single-dose infusion of the bispecific multivalent eCD4-based bnAb LSEVh-LS-F resulted in rapid virological control in chronically SHIV-infected macaques without the development of resistance.…”

Section: Discussionmentioning

confidence: 99%

Rapid Elimination of Broadly Neutralizing Antibodies Correlates with Treatment Failure in the Acute Phase of Simian-Human Immunodeficiency Virus Infection

Xue

Wang

et al. 2019

J Virol

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Early human immunodeficiency virus type 1 (HIV-1) treatment during the acute period of infection can significantly limit the seeding of viral reservoirs and modify the course of disease. However, while a number of HIV-1 broadly neutralizing antibodies (bnAbs) have demonstrated remarkable efficacy as prophylaxis in macaques chronically infected with simian-human immunodeficiency virus (SHIV), intriguingly, their inhibitory effects were largely attenuated in the acute period of SHIV infection. To investigate the mechanism for the disparate performance of bnAbs in different periods of SHIV infection, we used LSEVh-LS-F, a bispecific bnAb targeting the CD4 binding site and CD4-induced epitopes, as a representative bnAb and assessed its potential therapeutic benefit in controlling virus replication in acutely or chronically SHIV-infected macaques. We found that a single infusion of LSEVh-LS-F resulted in rapid decline of plasma viral loads to undetectable levels without emergence of viral resistance in the chronically infected macaques. In contrast, the inhibitory effect was robust but transient in the acutely infected macaques, despite the fact that all macaques had comparable plasma viral loads initially. Infusing multiple doses of LSEVh-LS-F did not extend its inhibitory duration. Furthermore, the pharmacokinetics of the infused LSEVh-LS-F in the acutely SHIV-infected macaques significantly differed from that in the uninfected or chronically infected macaques. Host SHIV-specific immune responses may play a role in the viremia-dependent pharmacokinetics. Our results highlight the correlation between the fast clearance of infused bnAbs and the treatment failure in the acute period of SHIV infection and may have important implications for the therapeutic use of bnAbs to treat acute HIV infections. IMPORTANCE Currently, there is no bnAb-based monotherapy that has been reported to clear the virus in the acute SHIV infection period. Since early HIV treatment is considered critical to restricting the establishment of viral reservoirs, investigation into the mechanism for treatment failure in acutely infected macaques would be important for the therapeutic use of bnAbs and eventually towards the functional cure of HIV/AIDS. Here we report the comparative study of the therapeutic efficacy of a bnAb in acutely and chronically SHIV-infected macaques. This study revealed the correlation between the fast clearance of infused bnAbs and treatment failure during the acute period of infection.

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“…The addition of the coreceptor-mimetic peptide also limits CD4enhancement on CD4-negative/CCR5-positive cells. Recently we have shown that three mutations in CD4 domain 1 increase its potency by an average of 9-fold (Fetzer et al, 2018). Furthermore, in vitro studies showed that continuous passaging of virus in the presence of eCD4-Ig only yielded partial resistance to the inhibitor (Fellinger et al, 2019).…”

Section: Engineered Hiv-1 Inhibitorsmentioning

confidence: 99%

Promise and Progress of an HIV-1 Cure by Adeno-Associated Virus Vector Delivery of Anti-HIV-1 Biologics

Gardner

2020

Front. Cell. Infect. Microbiol.

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Despite the success of antiretroviral therapy (ART) at suppressing HIV-1 infection, a cure that eradicates all HIV-1-infected cells has been elusive. The latent viral reservoir remains intact in tissue compartments that are not readily targeted by the host immune response that could accelerate the rate of reservoir decline during ART. However, over the past decade, numerous broadly neutralizing antibodies (bNAbs) have been discovered and characterized. These bNAbs have also given rise to engineered antibody-like inhibitors that are just as or more potent than bNAbs themselves. The question remains whether bNAbs and HIV-1 inhibitors will be the effective "kill" to a shock-and-kill approach to eliminate the viral reservoir. Additional research over the past few years has sought to develop recombinant adeno-associated virus (rAAV) vectors to circumvent the need for continual administration of bNAbs and maintain persistent expression in a host. This review discusses the advancements made in using rAAV vectors for the delivery of HIV-1 bNAbs and inhibitors and the future of this technology in HIV-1 cure research. Numerous groups have demonstrated with great efficacy that rAAV vectors can successfully express protective concentrations of bNAbs and HIV-1 inhibitors. Yet, therapeutic concentrations, especially in non-human primate (NHP) models, are not routinely achieved. As new studies have been reported, more challenges have been identified for utilizing rAAV vectors, specifically how the host immune response limits the attainable concentrations of bNAbs and inhibitors. The next few years should provide improvements to rAAV vector delivery that will ultimately show whether they can be used for expressing bNAbs and HIV-1 inhibitors to eliminate the HIV-1 viral reservoir.

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eCD4-Ig Variants That More Potently Neutralize HIV-1

Cited by 23 publications

References 53 publications

A Coreceptor-Mimetic Peptide Enhances the Potency of V3-Glycan Antibodies

A Coreceptor-Mimetic Peptide Enhances the Potency of V3-Glycan Antibodies

Rapid Elimination of Broadly Neutralizing Antibodies Correlates with Treatment Failure in the Acute Phase of Simian-Human Immunodeficiency Virus Infection

Promise and Progress of an HIV-1 Cure by Adeno-Associated Virus Vector Delivery of Anti-HIV-1 Biologics

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